Analgesic: 3, 4-dimethylbenzamide



United States Patent 3,086,911 ANALGESIC: 3,4-DIMETHYLBENZAMIDE Bernard Beau Brown, Westfield, and Wiliiam Glen Bywater, Upper Montclair, N.J., assignors to S. B.

Penick and Company, New York, N.Y., a corporation of Delaware No Drawing. Filed May 26, 1961, Ser. No. 112,776

Claims. (Cl. 167-65) This invention relates to processes for relieving pain in animals and is more particularly concerned with proccesses for relieving protopathic pain in humans.

At present the compositions used for the suppression of protopathic pain, particularly of the type caused by arthritis, are the salicylates such as sodium salicylate, aspirin, and salicylamide; the acetanilids such as acetophenetidin, acetyl-p-aminophenol and acetanilid; and the narcotics such as morphine, codeine and the like. The presently used salicylates and acetanilids do not provide a sufficient depth of analgesia to be fully effective. On the other hand, prolonged use of the more analgesic narcotics, such as codeine or morphine, may lead to narcotic addiction. The prolonged administrations of corticosteroids, also used in such circumstances, may give rise to undesirable side-effects, so profound as to necessitate discontinuance of the medication.

The present invention is based on the unexpected finding that 3,4-dimethylbenzamide exhibits analgesic activity when administered to the animal organism. Oral administration of dosage quantities of the compound to humans gives beneficial relief of protopathic pain without gastric distress or observable toxic, sedative, or hypotensive side-effects.

The invention sought to be patented resides in the concept of a method of mitigating protopathic pain in humans which comprises the oral administration of 3,4- dimethylbenzamide to a person suffering from protopathic pain, the average daily dose administered being in the range 0.5 to 3.0 grams.

The manner and process of making and using this invention is illustrated by the following general description and examples, which set forth the best mode contemplated by us of carrying out the invention so as to enable any person skilled in the art of pharmacodynamics to make and use the same:

In addition to its use in alleviating the protopathic aspects of pain in patients with arthritis, particularly osteroart-hritis, and in patients with myositis, we have discovered that 3,4-dimethylbenzamidedeepened and prolonged the analgetic effect of aspirin and phenacetin and that the aspirin and phenacetin enhanced the activity of 3,4-dimethylbenzamide resulting in an enhanced relief from pain. To illustrate:

Fifteen ambulatory patients having arthritis of various joints were given 3,4-dimethylbenzamide in dosages of 225 milligrams or 500 milligrams four times a day (0.9 to 2 grams daily). Within twenty-four hours all patients showed a fair alleviation of their pain. The addition of 5 grains of aspirin or 2.5 grains of phenacetin greatly intensified the analgetic response.

Not only was the analgesic effect potentiated, but it was lengthened in duration. The analgesia of the compounds was evaluated as compared to placebos administered to the same group of patients. In some patients with myositis or arthritic disturbances given the 3,4-dimethylbenzamide along with aspirin, 5 grains (300 milligrams), or phenacetin (150 milligrams), analgetic effects lasting from 8 to 15 hours were observed. In a group of-patients with acute viral myositis of the neck, following each dose of 500 milligrams of 3,4-dimethylbenzamide in combination with 300 milligrams of aspirin and/ or 150 ice milligrams of phenacetin, the patients obtained relief from pain that lasted twenty-four hours.

The prolongation and intensification effects of analgesics with 3,4-dimethylbenzamide has been noted with salicylates such as sodium salicylate and aspirin with aspirin as the preferred compound. It has also been noted with the acetanilids including acetanilid itself, as well as aceto phenetidin and n-acetyl-p-aminophenol. Of these, phenacetin appears to be the safest and most potent alone and in combination with 3,4-dimethylbenzamide.

The protopathic analgesic effects of 3,4-dimethylbenzamide have also been combined with the different analgesic effects of the narcotic derivatives related to opium such as codeine, morphine and meperidine. This combination provides analgesic protection against intense pains having both protopathic and epicritic components.

We have also found that 3,4-dimethylbenzamide lowers the body temperature in pyrexic rats when tested by the method of Boxhill et al., J. A. Ph. A., 47, 479 (1958). The response to the administration of 3,4-dimethylbenzamide is much more rapid than that of aspirin or salicylamide. This antipyretic effect was studied in humans; two pyretic patients suffering from nonspecific fevers had their temperature return to normal within three hours after the oral administration of 500 milligrams of 3,4- dimethylbenzamide.

In various series of patients to Whom the drug was administered either alone or in combination and in dosages rangin-g as high as 2 grams daily for periods up to one month, no signs of sedation, depression, hypnosis, gastric distress, or other untoward side-effects were noted due to the oral administration of 3,4-dimethylbenzamide. To illustrate:

3,4-dimethylbenzamide was administered to two series of hypertensive patients. The first series of 30 patients had severe hypertension with average blood pressures of 230/126 millimeters and had been under careful observation as hypertensives prior to the study. 3,4-dimethylbenzamide was administered orally to each patient in doses of 250 milligrams, four times a day. At the end of one month, these patients showed no average reduction in blood pressure and hence no hypotensive response to 3,4-dimethy1benzamide. In the second series, the patients having less severe hypertension with an average blood pressure of I00 millimeters, the administration of 3,4 dimethylbenzamide caused no significant decrease in blood pressure. This lack of hypertensive activity is of great value, since this material can be used routinely and safely as an analgesic or in combination with other analgesics without causing undesirable changes in blood pressure.

Possible sedative effects of 3,4-dimethylbenzamide were studied in 15 patients with various types of anxiety, insomnia, psychogenic headaches, urticaria, and in some spastic conditions. No clinically observable effects on these symptoms was noted in the group at doses of 225 milligrams or 500 milligrams, four times daily, when compared with a placebo.

3,4-dimethylbenzamide can be administered alone or in combination with the other analgetics. It may be administered by mouth in aqueous suspension or solutions, more conveniently in solid form via capsules and tablets. The following non-limiting series of formulations are illustrative of the proportions of ingredients required per 1000 tablets to give tablets suitable for oral administration:

FORMULATION A Grams 3,4-dimethylbenzamide 250 Lactose (diluent and compressant) 334 Starch (disintegrating agent) 60 Calcium stearate (lubricant) 6 The ingredients were mixed, granulated, dried, and compressed into tablets.

FORMULATION B The ingredients were mixed, granulated, dried, and then pressed into tablets.

FORMULATION C Grams 3,4-dimethylbenzamide 250 Aspirin granulation (20 percent corn starch) 375 Lubricant (polyethylene glycol) 15 The ingredients were mixed and then compressed directlyinto tablets.

FORMULATION D Grams 3,4-dimethylbenzamide 250 Phenacetin 150 Caffeine 30 Lactose 214 Calcium stearate 6 The ingredients were mixed and pressed directly into tablets.

FORMULATION E Grams 3,4-dimethylbenzamide 500 Codeine sulfate 15 Starch 60 Lactose 60 Calcium stearate 15 The formulation was mixed and directly pressed to yield tablets.

. FORMULATION F Grams 3,4-dimethylbenzamide 250 Aspirin 300 Phenacetin 150 Caffeine 30 Carbowax 20 Starch 100 The formulation was mixed and pressed into tablets.

The amount of 3,4-dimethylbenzamide in each dosage form depends on the frequency of administration, the intensity of the pain being treated, and the total daily amount of the therapeutic agents that it is desired to have administered. In general, the average daily dose for a human adult falls in the range 0.5 to 3.0 grams, preferably in the range 1.0 to 2.0 grams, when administered alone or in conjunction with the analgesics. The average daily dose is usually administered in divided doses, the dosage form conveniently containing 0.25 or 0.50 gram of 3,4-dimethylbenzamide.

The compound, 3,4-dimethylbenzamide, was first described by Gatterman, Annalen der Chemie, 224, 29 (1888), who prepared it via the aluminum chloride catalyzed reaction of o-xylene and carbamyl chloride and reported the melting point to be 131 degrees centigrade. We have repeated the Gatterman method and obtained 3,4-dimethylbenzamide melting at 111 to 112.5 degrees centigrade. A mixed melting point determination of this amide with a sample prepared via the unequivocal sequence 3,4-dimethylbromobenzene, 3,4-dimethylbenzonitrile, 3,4-dimethylbenzoic acid, 3,4-dimethylbenzoyl chloride to 3,4-dimethylbenzamide gave no lowering of the melting point. The infrared curves and nitrogen analyses were also identical. Hydrolysis of the amides yielded the known 3,4-dimethyl benzoic acid of melting point 4 166 degrees centigrade, identical to the acid prepared by other methods.

The following examples illustrate our preferred methods for the preparation of 3,4-dimethylbenzamide via 3,4-dimethylbenzonitrilc: (All of the temperatures are given in degrees centigrade and the pressures in millimeters of mercury.)

Example 1.Preparati0n of 3,4-Dz'm thylb nzonitrile Slowly heat to 225-230 degrees with stirring 27.75 grams of 4-bromo-o-xylene, 14.85 grams of cuprous cyanide, and 1.20 grams of pyridine. When the initial reaction is substantially complete as evidenced by the disappearance of the foam and the brown color of the reaction mixture, the reaction mixture is maintained at 230-232 degrees for an additional 3 hours and then cooled. Toluene is added and the mixture filtered. The precipitate is washed with hot toluene. The filtrate and wash liquors are combined and the toluene removed by evaporation. The residue is flash distilled under vacuum, 148-152 degrees at 54 millimeters. The 3,4-dimethylbenzonitrile thus obtained is recrystallized from ethanol to a melting point of 648-66 degrees.

Example 2.-Preparation of 3,4-Dimethylbenzamia'e Via the Acid 3,4-dimethylbenzonitrile is hydrolyzed in 75 milliliters of 10 percent aqueous sodium hydroxide solution containing 10 milliliters of ethanol by refluxing for 8 hours. The reaction mixture is cooled, diluted, and filtered. The filtrate, the sodium salt of 3,4-dimethylbenzoic acid, is neutralized with hydrochloric acid. The free acid is separated and recrystallized from aqueous alcohol to a melting point of 166-168 degrees.

To 9 grams of 3,4-dimethylbenzoic acid is added 15 grams of thionyl chloride. The mixture is refluxed for 3 hours after which the excess of thionyl chloride is removed by distillation under vacuum. The product, 3,4- dimethylbenzoyl chloride, has a boiling point of 129- degrees at 14-15 millimeters.

3,4-dimethylbenzoyl chloride is slowly added to concentrated ammonia. solution. The reaction mixture is maintained at 10-15 degrees for one hour. The mixture is then filtered and the cake washed with cold water at 5-10 degrees. The product, 3,4-dimethylbenzamide, is obtained in 97 percent yield and has a melting point range of 111.5-112.5 degrees.

Example 3.-Preparali0n of 3,4-Dimethylbenzamide by Oxidation of the Nitrile A flask equipped for heating and cooling is charged with 30 milliliters of ethanol and 33 grams of 30 percent hydrogen peroxide and its contents adjusted to pH 10 with sodium hydroxide. To this solution is added 10 grams of 3,4-dimethylbenzonitrile and the reaction mixture maintained at 48-50 degrees for 3 hours. The reaction mixture is then cooled to ice temperature and filtered. The precipitate is washed with ice water and then dried to yield 3,4-dimethylbenzamide having a melting point range of 111-113 degrees in 96 percent yield.

Various modifications of this invention will suggest themselves to one skilled in the art, and the invention is not to be limited to the above-offered illustrations. The subject matter which the applicants regard as their invention is particularly pointed out and distinctly claimed as follows:

1. The method of mitigating protopathic pain in animals which comprises the oral administration of 3,4- dimethylbenzarnide to an animal having protopathic pain.

2. The method of mitigating protopathic pain in humans which comprises the oral administration of dosage units of 3,4-dimethylbenzamide to a person suffering from protopathic pain.

3. The method of mitigating protopathic pain in humans which comprises the oral administration of 3,4-

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dirnethylbenzamide to a person suffering from protopathic pain, the average daily dosage administered being in the range 0.5 to 3.0 grams.

4. The method of mitigating protopathic pain in humans which comprises the oral administration of 3,4- dimethylbenzamide to a person suffering from protopathic pain, the average daily dose administered being in the range 1.0 to 2.0 grams.

6 5. The method of mitigating protopathic pain in humans which comprises the oral administration of 3,4- dimethylbenzamide in divided doses to a person suffering from protopathic pain, the average daily dose administered 5 being in the range 1.0 to 2.0 grams.

References Cited in the file of this patent Chem. Abst., v01. 51, 1957, p. 17814f. 

1. THE METHOD OF MITIGATING PROTOPATHIC PAIN IN ANIMALS WHICH COMPRISES THE ORAL ADMINISTRATION OF 3,4DIMETHYLBENZAMIDE TO AN ANIMAL HAVING PROTOPHATHIC PAIN. 